The invention relates generally to androgenic and/or estrogenic inhibitor compounds, their use in the inhibition of C.sub.17-20 lyase, C.sub.17.alpha. -hydroxylase and 5.alpha.-reductase, and a method for the preparation of 4-amino-.DELTA..sup.4 -3-ketosteroids.
Androgenic and estrogenic biosynthesis is principally controlled by the action of the dual acting enzyme steroid C.sub.17-20 lyase and C.sub.17.alpha. -hydroxylase. While C.sub.17-20 lyase catalyses the conversion of steroids having a two carbon side chain at the 17.beta.-position, C.sub.17.alpha. -hydroxylase places a hydroxyl group of such a molecule at the 17.alpha.-position. The action of C.sub.17-20 lyase creates important precursor molecules to the formation of testosterone, 5.alpha.-dihydrotestesterone and the estrogens, principally estrone and estradiol. Effective inhibition of C.sub.17-20 lyase would be useful in inhibiting the formation of both androgenic and estrogenic steroids, and thus is useful in the treatment of disease states or disorders where said androgens and/or estrogens play an adverse role.
The enzyme steroid 5.alpha.-reductase catalyzes the conversion of testosterone into dihydrotestosterone or DHT (17.beta.-hydroxy-5.alpha.-androstan-3-one). DHT is a more potent androgen than testosterone and acts as an end-organ effector in certain tissues, particularly in mediating growth. Effective inhibition of this enzyme would be useful in preventing the formation of DHT, which thus is useful in the treatment of androgen dependent disorders, particularly those in which DHT plays a principal adverse role.
As the previously mentioned inhibitors affect various steps of the androgenic and/or estrogenic pathway, each with known therapeutic utility in the treatment of various androgen and/or estrogen dependent disorders, an alternative technique for the synthesis of said inhibitors would also be useful. Certain of the 4-aminosteroid derivatives which may be obtained by the process described in this application are disclosed in U.S. Pat. No. 4,757,061, issued Jul. 12, 1988, U.S. Pat. No. 5,120,840, issued Jun. 9, 1992 and U.S. Pat. No. 5,143,909, issued Sep. 1, 1992. The disclosed three step synthesis of these compounds involves formation of a 4,5-epoxysteroid derivative followed by treatment with sodium azide to provide the 4-azidosteroid derivative. The 4-azidosteroid derivative is subsequently reduced to provide the 4-aminosteroid derivative. The use of sodium azide in this synthesis involves health risks due to the inherent instability of the compound. A skilled chemist can safely carry out the above process on a small scale in the laboratory, because only a small quantity of sodium azide is used. However, the large scale industrial production of the 4-aminosteroid derivative requires large amounts of sodium azide and its derivative acid, hydrazoic acid. This synthesis, which requires large quantities of sodium azide and hydrazoic acid at elevated temperatures poses significant risks to human life and the environment. The environmental and health risks could be reduced through appropriate design of a chemical plant, however the cost of such a facility would be prohibitive and the inherent risks could still not be entirely eliminated. The three step synthesis of a 4-amino-.DELTA..sup.4 -steroid via the 4 azido-intermediate is graphically illustrated in Scheme A. ##STR3##
Previous attempts at nitrating .DELTA..sup.4 -3-ketosteroids, described by Schaub, et al. in Tetrahedron 20:373 (1964) and by Suginome et al. J. Bull. Chem. Soc. Jap. 62:1343 (1989), resulted in formation of the corresponding 2-nitrosteroid. This is suggested to have occurred because the nitration is effected through the kinetic 2,4-dienolate rather than the 3,5-dienolate which is the thermodynamic dienolate. The creation of 4-nitrosteroids would require conditions which are supportive to generation of a 3,5-dienolate as opposed to the 2,3-dienolate.